chr8-1858005-G-C
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_014629.4(ARHGEF10):āc.83G>Cā(p.Gly28Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.0000096 ( 0 hom. )
Consequence
ARHGEF10
NM_014629.4 missense
NM_014629.4 missense
Scores
2
11
3
Clinical Significance
Conservation
PhyloP100: 8.19
Genes affected
ARHGEF10 (HGNC:14103): (Rho guanine nucleotide exchange factor 10) This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.25784105).
BS2
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGEF10 | NM_014629.4 | c.83G>C | p.Gly28Ala | missense_variant | 3/29 | ENST00000349830.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARHGEF10 | ENST00000349830.8 | c.83G>C | p.Gly28Ala | missense_variant | 3/29 | 1 | NM_014629.4 | P4 | |
ARHGEF10 | ENST00000518288.5 | c.155G>C | p.Gly52Ala | missense_variant | 4/30 | 1 | |||
ARHGEF10 | ENST00000520359.5 | c.83G>C | p.Gly28Ala | missense_variant | 3/28 | 1 | A2 | ||
ARHGEF10 | ENST00000398564.5 | c.155G>C | p.Gly52Ala | missense_variant | 3/29 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152098Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727238
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74436
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with ARHGEF10-related conditions. This variant is present in population databases (rs547614439, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 28 of the ARHGEF10 protein (p.Gly28Ala). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;T;T
Polyphen
D;D;.;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.204);Gain of solvent accessibility (P = 0.204);.;.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at